Diabetes is called a contemporary national affliction as the central core of lifestyle-related diseases, and there is a pressing need to develop methods for its prevention and treatment. While the mechanism of onset of the disease has not yet been elucidated, it is considered that two pathological conditions of deficiency of insulin as a hormone for lowering the blood glucose level (impaired insulin secretion) and impaired insulin action (insulin resistance) are complicated. Diabetes is generally classified into (1) type 1 caused by the destruction of insulin-secreting pancreatic β cells and requiring continuous replenishment of insulin; (2) type 2 associated with deficient secretion of insulin or deteriorated action of insulin; (3) other types of diabetes induced by specific causes; (4) gestational diabetes, and the like.
Type 1 diabetes is one of autoimmune diseases, and also clinically termed insulin dependent diabetes. In this type, pancreatic β-cells that secrete insulin are attacked and destroyed by the autoimmune system. Insulin is a hormone that acts to lower blood glucose levels by absorbing glucose into the cells. Where insulin secretion is suppressed, blood glucose levels are elevated and cells become glucose deficient. Then, the cells cannot maintain their life activities when such a glucose-deficient state persists to cause impairments of various organs, loss of sight and foot necrosis. The model mouse of type 1 diabetes is known in the art, and studies on the therapy of type 1 diabetes have also been advanced using the mouse model (for example, see Science, 2003, Nov. 14, 302 (5648): 1223-7).
From the clinical point of view, Type 2 diabetes is often called as insulin independent diabetes and develops due to impaired insulin secretion in the pancreatic β-cells and insulin resistance. Which one of impaired insulin secretion and insulin resistance is strongly associated with type 2 diabetes differs depending upon respective cases or the process of each case, and both are often complicated. In normal subjects, glucose is absorbed after a meal and when blood sugar levels begin to elevate, insulin is secreted immediately in response the elevated glucose level, whereas in the impaired insulin secretion this response is lacking and insulin is secreted late after the increase in blood sugar levels.
Type 2 diabetes develops from relative deficiency of insulin action. In many cases, systemic insulin resistance is observed and, recently the relation of obesity, overeating or lack of exercise to the systemic insulin resistance, which was earlier only empirically understood, has been elucidated on a molecular level. Insulin resistance is defined as “a condition in which responsiveness of an insulin-sensitive cell or organ to insulin on a physiological level is reduced” and is positioned at the uppermost stream in the pathophysiology of type 2 diabetes.
Adipose tissue was simply understood as a mere energy reservoir so fax but has been recently recognized as a major endocrine organ in living subjects, actually producing various physiologically active substances, which are collectively referred to as adipocytokine. In particular, it was made clear that dysfunction of adipocytes associated with an overaccumulation of visceral fat in obesity, namely, abnormality of adipocytokine secretion (e.g., oversecretion of inflammatory cytokine TNFα, reduced secretion of adiponectin, etc.) induces insulin resistance, which plays an important role as various causes of pathological conditions of type 2 diabetes and arteriosclerotic diseases. Recently, it has been found that macrophages infiltrate and invade the adipose tissue to secrete inflammatory cytokine in white adipose tissue and as a result, induce insulin resistance, which draws attention to pathological physiology of myeloid cells latently present in adipose tissue.
Insulin receptor is localized to caveolae microdomain of cell membrane which is formed by accumulating a lipid group having a high phase transition temperature such as gangliosides (sphingoglycolipids), sphingomyelins, cholesterol, etc. A major ganglioside in adipose tissue is termed GM3. It is reported that the expression of ganglioside GM3 and its synthase gene is significantly up-regulated in adipose tissue stimulated with TNFα as well as in adipose tissue of typical obese diabetic model animals (Tagarni, et al., J. Biol. Chem., Vol. 277, 3085-3092, 2002). In addition, the relationship between the insulin metabolic signaling defect and a loss of insulin receptors in the microdomains due to an overaccumulation of GM3 is also reported (Kabayama et al., Glycobiology, Vol. 15, 21-29, 2005).
On the other hand, presently hematological diagnosis of type 2 diabetes is generally made by using blood glucose, HbAlc and glycoalbumin levels, etc. as indicators. The blood glucose level is a value obtained by measuring a glucose concentration in blood. HbAlc means a glycated protein in which glucose binds to hemoglobin in erythrocyte and is measured as the ratio of glycated protein to the total hemoglobin. HbAlc is considered to reflect the blood glucose control condition during the previous one or two months from the erythrocyte life span (120 days).
In addition, glycoalbumin (GA) is considered to reflect the blood glucose control condition from the previous two weeks to one month because the half-life period of albumin is 17 days. When compared with HbAlc, glycoalbumin can be observed more quickly with a larger change and is useful as an indicator to assess therapeutic effects and drug dosage.
In order to accurately assess the condition of type 2 diabetes, however, it is required to combine these measurement methods.
Furthermore, Harashima, et al. discloses the method of diagnosis by expression analysis of various genes in Published Japanese Patent Application KOKAI No. 2005-253434. However, in the case of this method, the diagnosis requires the expression analysis of various genes and cannot be made in a simple way.